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Blockade of the programmed death-1 (PD1) pathway undermines potent genetic protection from type 1 diabetes

Nora M Kochupurakkal1, Annie J Kruger2, Sudipta Tripathi1

  • 1Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School Renal Division, Boston, Massachusetts, United States of America.

Plos One
|March 4, 2014
PubMed
Abstract

Insights

Blocking PD1-PDL1 signaling accelerates type 1 diabetes in NOD mice, revealing how Idd genes and PD1 signaling collaborate to protect against this autoimmune disease.

Area of Science:

  • Immunology
  • Genetics
  • Endocrinology

Background:

  • The programmed cell death protein 1 (PD1)-programmed death-ligand 1 (PDL1) pathway is crucial in immune regulation.
  • Inhibition of PD1-PDL1 signaling accelerates type 1 diabetes in NOD mice, suggesting its role in preventing autoimmune T-cell responses against pancreatic beta cells.

Purpose of the Study:

  • To investigate the molecular mechanisms by which PD1 signaling protects against type 1 diabetes.
  • To identify genomic loci that collaborate with PD1 signaling in suppressing type 1 diabetes by examining differential susceptibility of Idd mouse strains to anti-PDL1 treatment.

Main Methods:

  • NOD and various Idd mouse strains were treated with anti-PDL1 at 10 weeks of age.
  • Disease onset was monitored by blood glucose levels; pancreatic insulitis was assessed histologically.
  • Statistical analysis included Log-Rank and Student's t-tests.

Main Results:

  • Anti-PDL1 treatment rapidly induced type 1 diabetes in most NOD Idd congenic strains, even those with protective Idd genes.
  • The Idd3/5 strain, highly protected from spontaneous disease, remained normoglycemic after PDL1 blockade.
  • Basal insulitis levels correlated with increased susceptibility to anti-PDL1-induced type 1 diabetes.

Conclusions:

  • Multiple Idd loci cooperate with PD1 signaling to confer protection against type 1 diabetes.
  • Anti-PDL1 therapy diminishes the protective effects of Idd genes in the NOD model.
  • These findings highlight the significance of the PD1 pathway in type 1 diabetes pathogenesis and its potential as an immunotherapy target.

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